Acute hypoxic respiratory failure secondary to antisynthetase syndrome: A case report and review of literature.

OBJECTIVE: Antisynthetase syndrome is a condition that includes interstitial lung disease and inflammatory myositis in its definition. The interstitial lung disease of this syndrome can vary in severity and if not identified soon enough, can lead to severe respiratory failure. Here we present a patient who had a working diagnosis of acute eosinophilic pneumonia. He initially improved after prolonged hospitalization and course of high dose steroids. CT chest revealed interval improvement in his bilateral ground glass and reticular opacities but residual fibrotic interstitial lung disease. However, he decompensated subsequently with relapsed hypoxia during activity. We hope that this review will bring awareness to antisynthetase syndrome and provide tools for earlier diagnosis and treatment. The primary objective of this study was to review presenting symptoms, diagnosis, treatment and outcomes. This review is unique because we focused on antisynthetase syndrome that initially manifested with lung symptoms rather than myositis or skin changes.
METHODS: We have performed a comprehensive review of 30 cases of antisynthetase syndrome in the literature (including our case).
RESULTS: Total 30 cases reported, 17 male patients and 13 female patients. Only 43% of the cases presented with lung symptoms alone, while 57% of the cases presented with lung and muscle symptoms simultaneously.
CONCLUSION: This supports the fact that antisynthetase syndrome most commonly presents with lung and muscle manifestations simultaneously. The fact that our case presented with lung findings alone led to the delay in his diagnosis.

Introduction

Antisynthetase syndrome is a rare but significant cause of interstitial lung disease. It most commonly presents in middle-aged women. The triad of antisynthetase syndrome includes interstitial lung disease, inflammatory myositis and presence of antisynthetase antibodies (aminoacyl-transfer RNA synthetase antibodies). These antibodies are directed against enzymes that attach amino acids to their associated transfer ribonucleic acid during polypeptide synthesis. So far, 8 different antibodies have been identified [1]. The most common antibody is Anti-Jo-1, next are anti-PL-7 and anti-PL-12 [2]. These are associated with histidine, threonine and alanine respectively [3]. Anti-Jo-1 antibody is named after a patient affected with interstitial lung disease and polymyositis by scientists in 1980. When a patient has one of these antibodies it is highly specific for antisynthetase syndrome. Antisynthetase syndrome is known for its acute disease onset but is most often a delayed diagnosis. The delay in diagnosis stems from varying degrees of symptomatology and features that are in common with other forms of interstitial lung disease (ILD). Early diagnosis can improve outcomes of this disease. We report a case of antisynthetase syndrome in which the patient presented with solely pulmonary symptoms (see Fig. 1).

Fig. 1

Our patient’s chest imaging during his initial presentation. Chest X-ray (11/05/17) “Mild pulmonary venous congestion, small bilateral pleural effusions with associated bibasilar atelectasis.” CT chest (11/13/17) “airspace consolidation and ground-glass throughout the lungs, greatest in the lung bases (acute pneumonia, organizing pneumonia, acute eosinophilic pneumonia), bilateral lung base bronchiectasis.”

Case presentation

The patient is a 61 year old male who presented to an outside facility with productive cough, dyspnea and pleuritic chest pain of one month duration. No rash or joint pain were described. Past medical history included hypertension and regular alcohol use. Patient was a former smoker and worked at a printing company. He denied any exposure to dust or fumes at his job. He reported that he was building a wood shelter for hunting outside when he began to have a dry cough and dyspnea. He was given oral antibiotics and prednisone by his primary care doctor but his symptoms did not improve. His vitals on initial presentation were notable for hypoxia to 80% on room air. Lung exam was notable for bilateral infrascapular crackles and bronchial breath sounds. He had a respiratory alkalosis and hypoxia with pH 7.49, PCO2 31.3 mmHg, HCO3 24.8 mEq/L, PO2 61.6 mmHg. CT angiography of the chest revealed patchy bibasilar opacities, scattered bilateral ground glass and nodular opacities but no pulmonary embolism. He was started on broad spectrum antibiotics (IV vancomycin, piperacillin-tazobactam, levofloxacin) and continued on them after transfer to our facility.

Infectious workup was largely negative. Influenza PCR was negative. Blood cultures, sputum culture, lactic acid, procalcitonin, urinalysis were all negative. Legionella, Mycoplasma, Histoplasmosis, Coccidioides, Aspergillosis and Chlamydia pneumonia studies were negative. Patient had a negative ANCA but positive ANA (1:40). Briefly after admission to our facility, patient had continued hypoxia on 15 L nonrebreather mask. He was subsequently transferred to the ICU, intubated and placed on mechanical ventilation. ICU stay was complicated by acute kidney injury and hypotension. After 3 days of broad spectrum antibiotics and no improvement, as well as negative cultures, patient was started on itraconazole 200 mg three times daily for fungal coverage. Bronchoscopy was done and revealed increased eosinophils in bronchoalveolar lavage (BAL), concerning for eosinophilic pneumonia. He was started on IV methylprednisolone 60 mg every 6 hours on 5th day of hospitalization. On day 8 of hospitalization, patient was extubated and transferred out of the ICU. Patient initially had a difficult time being weaned off oxygen via nasal cannula but eventually improved. Steroid was eventually tapered down to prednisone 30 mg qday at discharge. Repeat CT of the chest revealed airspace consolidation and ground-glass opacities throughout the lungs (greatest at the bases) along with bilateral lung base bronchiectasis, improved from previous. Patient was treated with 3 week course of oral fluconazole 200 mg daily for laryngeal thrush. Patient had significant muscle weakness and difficulty standing after prolonged hospitalization. He was discharged to a physical rehabilitation facility and close follow-up with Pulmonology was arranged. Patient was discharged with the diagnosis of acute eosinophilic pneumonia because of his predominant eosinophils on BAL but also his clinical improvement on IV steroids. He remained on 2 L of oxygen via nasal cannula while on an oral steroid taper. He was continued on oral prednisone 30 mg once daily until his scheduled pulmonology follow-up 9 days after discharge.

At this first outpatient Pulmonology visit, patient was saturating 89% on 2L oxygen and was unable to stand or walk by himself. He was continued on prednisone 30 mg once daily for another month. He was then changed to prednisone 20 mg daily and was seen in the office 10 days after this change. His respiratory status was stable. He was continued on an oral prednisone taper. Patient presented to the outpatient Pulmonology office 6 weeks later with worsening respiratory status. He desaturated to 78% on room air during activity and required increased oxygen at rest (2 L–4 L). At the time he was on prednisone 15 mg once daily. He was changed back to 40 mg daily.

Patient was subsequently referred to a tertiary care center for further evaluation due to his failure to improve after empiric treatment for eosinophilic pneumonia. He was evaluated by both Pulmonology and Rheumatology. Repeat CT of the chest without contrast reported extensive patchy ground-glass and reticular opacities throughout both lungs (improved), compatible with sequelae of prior eosinophilic or organizing pneumonia. Repeat BAL revealed normal oral flora without eosinophilia. Patient tested positive for Anti-Jo-1 antibody, had elevated aldolase, mildly elevated CK (476 U/L) and positive ANA. At this point, he was diagnosed with antisynthetase syndrome. He was in physical rehabilitation after his discharge but continued to have weak hip flexors and difficulty with activity on his own. An EMG or muscle biopsy was considered but not done. Therefore it is unclear if he had the myositis component of antisynthetase syndrome. He did exhibit other signs of autoimmune disease including Raynaud's phenomenon.

Throughout this workup, patient continued to take his oral prednisone taper initiated during his initial hospitalization. Additional therapy was warranted due to his symptoms, which included hypoxia and severe restrictive lung disease. Cyclophosphamide was initiated, with dosing of 100 mg each morning for 3 days, 150 mg each morning for 3 days then to a target dose of 175 mg. He was started on oral sulfamethoxazole-trimethoprim double-strength 160–800 mg qday for Pneumocystis jiroveci pneumonia (PJP) prophylaxis. He continues to follow with his physicians at the tertiary care center. Patient was on cyclophosphamide for 6 months and has now transitioned to mycophenolate. He was weaned off oxygen after initiation of cyclophosphamide. He reports that he is now playing golf again without difficulty (see Table 1).

Table 1

Our patient’s spirometry completed on 4/23/18, 5 months after his initial hospitalization and 2 days before initiation of cyclophosphamide treatment.

	Pre-Bronchodilator		Post-Bronchodilator
	Measured	% Predicted	Measured	% Predicted
FVC (L)	2.09	47%	2.13	48%
FEV1 (L)	1.74	51%	1.82	54%
FEV1/FVC (%)	83.4	108	85.7	110
DLCOcSB (ml/mmHg/min)	Not applicable		7.5	27%

Materials and methods

Ethics board approval was waived because research was not done on active human participants. We obtained our patient's written consent to publish this material, including his case presentation, hospital course and treatment outcomes as described. We used PubMed and the American College of Chest Physicians for our online literature search. We reviewed 30 cases of antisynthetase syndrome in the literature (including our case). Inclusion criteria included lung symptoms as an initial presenting symptom. We excluded studies that had muscle symptoms alone and cases without any lung symptoms at all. Characteristics from each paper including demographics, presentation, symptoms, imaging, serologic tests, diagnosis, treatment and outcomes were compiled into Table 2.

Table 2

Compilation of 30 case reports including our case: Demographics, presentation, signs/symptoms, serologic tests, diagnostic tests, treatment, outcomes, markers of improvement [[1], [2], [3], [4], [5], [6], [7], [8],[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]]. ** = out of the 26 cases that disclosed outcomes.

Demographics		Biopsy
Age	32–77	Muscle biopsy	8/30 (27%)
Male	17/30 (57%)	Lung biopsy	10/30 (33%)
Female	13/30 (43%)	Skin biopsy	2/30 (7%)
Initial presentation		Treatment
Lung symptoms only	13/30 (43%)	Steroids	29/30 (97%)
Muscle symptoms only	0/30 (0%)	Cyclophosphamide	11/30 (37%)
Lung & muscle simultaneously	17/30 (57%)	Azathioprine	3/30 (10%)
Signs/Symptoms		Mycophenolate Mofetil	8/30 (27%)
Cough	22/30 (73%)	Methotrexate	3/30 (10%)
Fever	12/30 (40%)	Rituximab	4/30 (13%)
Shortness of breath	26/30 (87%)	Tacrolimus	3/30 (10%)
Hypoxia	14/30 (47%)	Outcomes
“Mechanic's hands”	12/30 (40%)	Resolved	3/30 (10%)
Arthralgia	8/30 (27%)	Improved	23/30 (77%)
Muscle weakness/myalgia	13/30 (43%)	Not disclosed	3/30 (10%)
Findings on CT of the chest		Expired	1/30 (3%)
Bilateral lung infiltrates	30/30 (100%)	Markers of improvement**
Ground glass opacities	18/30 (60%)	Resolution of symptoms	11/26 (42%)
Traction bronchiectasis	8/30 (27%)	Decreased inflammatory markers	3/26 (12%)
Serologic tests		Clearance of infiltrates on chest imaging	2/26 (8%)
ANA	11/30 (37%)	Combination of the above 3	10/26 (38%)
Anti-Jo-1	18/30 (60%)
Anti-Ro	7/30 (23%)
Anti-CCP	3/30 (10%)
Rheumatoid factor	5/30 (17%)
Anti-PL-7	7/30 (23%)
Anti-PL-12	3/30 (10%)

Results

We completed a comprehensive review of 30 cases of antisynthetase syndrome in the literature (including our case). Total 30 cases reported, 17 male patients and 13 female patients. Only 43% of the cases presented with lung symptoms alone [2,4,7,10,[16], [17], [18],[23], [24], [25],29,32], while 57% of the cases presented with lung and muscle symptoms simultaneously [1,5,8,[11], [12], [13], [14], [15],[19], [20], [21], [22],[26], [27], [28],30,31]. We did not review any cases that presented with muscle symptoms alone. This supports the fact that antisynthetase syndrome most commonly presents with lung and muscle manifestations simultaneously. The fact that our case presented with lung findings alone led to the delay in his diagnosis. The most predominant presenting symptoms included cough (73%), shortness of breath (87%) and hypoxia (47%). Other findings are described including fever, arthralgia, muscle weakness, myalgia and mechanic's hands. Every patient had CT chest findings that were bilateral, while 60% of patients exhibited ground glass opacities. Traction bronchiectasis was found in 27% of patients. There is no official diagnostic criteria for antisynthetase syndrome, however diagnostic tests found in these cases lean towards serologic testing as a way to confirm the diagnosis. The most prevalent serologic tests were Anti-Jo-1 (60%) and ANA (37%). Other positive tests included Anti-Ro, Anti-CCP, Rheumatoid factor, Anti-PL-7 and Anti-PL-12. Anti-Jo-1 antibody is considered a specific marker for antisynthetase syndrome. This antibody is typically found in 20–30% of patients with polymyositis but in 60–70% of patients with concomitant interstitial pulmonary fibrosis. The average sensitivity and specificity for anti-Jo-1 antibody is 22% and 99% [9]. The pathophysiology of how anti-Jo-1 antibody or any other antibody relates to the severity of disease is unknown. In addition to antibody testing, a majority of clinicians in the patient cases pursued a pathologic diagnosis with lung biopsy, muscle biopsy or skin biopsy. Lung biopsy was performed in 33% of patients. Despite that, many cases noted the desire for a lung biopsy but the inability to pursue due to patient's declining respiratory status. Findings in lung biopsy included interstitial pneumonia, inflammatory infiltrates, fibrosis, alveolar damage and thickened alveolar septae. The predominant treatment modality for antisynthetase syndrome is immunosuppression. While the etiology of antisynthetase syndrome is unclear, it is associated with other autoimmune diseases in the symptomatology and laboratory testing. The two predominant medications used in this review were steroids (97%) and cyclophosphamide (37%). Out of the 30 cases, 10% of patients had their condition resolve completely, 77% had improvement, 3% expired and 10% of patients did not have their outcome disclosed.

Discussion

Clinicians should be aware of antisynthetase syndrome and its manifestation. This case is an example of how a broad differential diagnosis should be considered, especially when patients do not respond to standard therapy [4]. In a patient with acute onset pneumonia and respiratory distress, the more common etiologies should be worked up first. However, if workup for bacterial, fungal and viral etiologies come up negative, autoimmune and inflammatory conditions should remain on the differential. Diagnostic criteria for antisynthetase syndrome includes a positive anti-aminoacyl-tRNA antibody along with 2 of the three following: interstitial lung disease, inflammatory myopathy, inflammatory polyarthritis. There are multiple patterns of interstitial lung disease in antisynthetase syndrome. These include nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), diffuse alveolar damage (DAD), organizing pneumonia (OP) and acute interstitial pneumonia (AIP) [5]. NSIP is the most common in antisynthetase syndrome [6]. DAD is the characteristic pneumonia of eosinophilic pneumonia. Diagnosis is most commonly made by antibody testing, high resolution CT scan, lung biopsy or any combination of the three. Biopsy may be limited by patient's clinical condition. High resolution CT scan of the chest is most commonly done when interstitial lung disease is suspected. The most common findings on CT scan include ground glass opacifications, peribronchial consolidations and find nodularity [7]. Fibrosis is a negative prognostic indicator in antisynthetase syndrome [8].

Treatment modalities vary depending on the severity of the patient's interstitial lung disease. This is reflected in imaging, PFTs and clinical symptoms. Muscle and bone involvement does not necessarily correlate with disease severity. Systemic glucocorticoids (IV or oral) are first line treatment. If respiratory failure continues to worsen on steroids, patients require other types of immunosuppression for treatment. Options include azathioprine, mycophenolate mofetil and cyclophosphamide. One important thing to note is the patient's level of thiopurine methyltransferase. Mycophenolate is favored in patients with a low level of thiopurine methyltransferase. Our patient had a normal level of thiopurine methyltransferase. The prognosis of antisynthetase syndrome is not widely studied. However, it is thought that with rapid diagnosis and treatment along with close monitoring, patients can make a full recovery. Antisynthetase syndrome and eosinophilic pneumonia are extremely similar with regards to symptoms, imaging studies, laboratory testing as well as diagnostic studies, including bronchoalveolar lavage. This was demonstrated in the diagnostic process of our patient case.

We had several limitations that contributed to our delay in diagnosis. These included low prevalence of antisynthetase syndrome in our patient population, lack of knowledge with the diagnostic criteria and treatment modalities and an initial working diagnosis that ceased investigation into other etiologies. Patient had an initial delay in his diagnosis, about 4–5 months, because of our inability to recognize antisynthetase syndrome. While the patient improved clinically after referral to another facility, this delay in diagnosis prompted us to look at how we evaluate patients who come in with acute hypoxic respiratory failure.

Antisynthetase syndrome is a complex autoimmune disorder diagnosed and treated by Pulmonologists and Rheumatologists. Official diagnostic criteria may not be established, and many centers may not have the ability to test for antisynthetase antibodies. However, we believe that this review of literature will provide the knowledge and tools for clinicians to identify and treat antisynthetase syndrome.

Conclusion

Antisynthetase syndrome should always be considered when treating a patient for acute respiratory failure with characteristics of interstitial lung disease. Our patient's disease process and time until treatment with adequate immunosuppression was prolonged due to delay of diagnosis. We anticipate that as the awareness of this syndrome grows and more research is completed, this can help guide recognition, diagnosis and treatment of antisynthetase syndrome.

Conflicts of interest

We have no conflicts of interest to disclose. Ethics board approval was waived because research was not done on active human participants. We obtained our patient's written consent to publish this material, including his case presentation, hospital course and treatment outcomes as described. We used PubMed and the American College of Chest Physicians for our online literature search. We reviewed 30 cases of antisynthetase syndrome in the literature (including our case).